RU2260586C2 - Ligands of thyroid receptors: derivatives of aniline - Google Patents

Abstract

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to preparing new ligands of thyroid receptors of the general formula:

wherein X means oxygen (-O-); Y means -(CH₂)_n-; n means a whole number from 1 to 3; or -C=C- that represents cis- or trans-isomer. R₁ means alkyl comprising 3-6 carbon atoms; R₂ and R₃ are similar or distinct and mean hydrogen, halogen atom, alkyl comprising 1-4 carbon atoms wherein at least one of R₂ and R₃ doesn't mean hydrogen atom; R₄ means hydrogen atom or lower alkyl; R₅ means hydrogen atom; R₆ means carboxylic acid or its ester; R₇ means hydrogen atom and including its all stereoisomers or its pharmaceutically acceptable salt. New compounds can be useful for prophylaxis, suppression or treatment of disease caused by the metabolism dysfunction or the expression of T₃-regulated gene, for example, such diseases as obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmia, depression, osteoporosis, hypothyroidism, goiter, thyroid gland cancer, glaucoma, congestive cardiac insufficiency and skin injures.

EFFECT: valuable medicinal properties of ligands.

19 cl, 1 tbl, 19 ex

Description

This invention relates to new compounds that are ligands of the thyroid hormone receptor and are preferably selective relative to the thyroid hormone β-receptor a, and to methods of using such compounds, for example, to regulate metabolism.

Although the exclusive role of thyroid hormones in regulating the human metabolic process is well known, the creation and improvement of new specific drugs for the more successful treatment of hyperthyroidism and hypothyroidism is very slow. It also limits the creation of thyroid agonists and antagonists for the treatment of other important clinical indications, such as hypercholisterinemia, obesity and cardiac arrhythmias.

Thyroid hormones affect the metabolism of almost every cell in the body. At normal levels, these hormones support body weight, metabolic rate, body temperature and mood and affect serum levels of low density lipoprotein (LDL). So, with hypothyroidism, body weight increases, high LDL cholesterol levels and depression are characteristic. With excess in case of hyperthyroidism, these hormones cause weight loss, hypermetabolism, decreased serum LDL levels, arrhythmia, heart failure, muscle weakness, postmenopausal women osteoporosis and anxiety.

Currently, thyroid hormones are used, first of all, as replacement therapy in patients with hypothyroidism. L-thyroxine therapy returns normal metabolic functions and can be easily monitored by routine measurements of thyrotropin (TSH), thyroxine (3,5,3 ', 5'-tetraiod-L-thyronine, or T ₄ ) and triiodothyronine (3,5,3'-triiod-L-thyronine, or T ₃ ). However, replacement therapy, especially in the elderly, is limited due to the harmful effects of thyroid hormones.

In addition, some effects of thyroid hormones can be therapeutically useful in non-thyroid disorders if harmful side effects are minimized or eliminated. Potentially applicable effects include weight loss, lowering serum LDL levels, lessening depression, and stimulating bone formation. Previous attempts to pharmacologically use thyroid hormones to treat these disorders have been limited by manifestations of hyperthyroidism, and especially cardiovascular toxicity.

The development of specific and selective agonists of thyroid hormone receptors could lead to specific agents for the treatment of these common disorders, while avoiding cardiovascular and other types of toxicity of natural thyroid hormones. Tissue-selective thyroid hormone agonists can be obtained by selective uptake or displacement of tissue, local or local delivery, targeting cells with other ligands attached to the agonist, and targeting receptor subtypes. Thyroid hormone receptor agonists that selectively interact with the β-form of the thyroid hormone receptor "offer" a particularly attractive way to avoid cardiotoxicity.

Thyroid hormone receptors (TRs) are, like other nuclear receptors, single polypeptide chains. The different receptor forms are apparently the “products” of two different genes, α and β. Additional differences in isoforms are due to the fact that differential RNA processing leads to at least two isoforms of each gene. Isoforms of TRα ₁ , TRβ ₁ and TRβ ₂ bind thyroid hormone and behave as ligand-regulated transcription factors. In an adult, the TRβ ₁ isoform is the most widespread form in most tissues, especially in the liver and muscles. TRα-form predominates in the pituitary gland and other areas of the central nervous system, does not bind thyroid hormones, and in many situations behaves as a transcription inhibitor. The TRα ₁ isoform is also widespread, although its levels are significantly lower than the levels of the TRβ ₁ isoform. This isoform can be especially important for improvement. Although many mutations were found in the TRβ gene and cause the syndrome of general resistance to thyroid hormone, mutations leading to a weakened TRα function were not found. Numerous data suggest that many or most of the effects of thyroid hormones acting on the heart, and in particular on the frequency and rhythm of heart contractions, are mediated through the α-form of the TRα ₁ isoform, while the effect of the hormone, for example, on the liver, muscles and other tissues are mediated mainly by the β-form of the receptor. Therefore, the TRβ-selective agonist does not seem to detect the effect of hormones on the frequency and rhythm of heart contractions, but it does reveal many other hormone actions. It is believed that the α-formoreceptor is the main form that affects heart rate, for the following reasons:

tachycardia is a common occurrence in the syndrome of general resistance (resistance) to thyroid hormone, in which TR β-forms are defective and high calculated levels of T ₄ and T ₃ ;

only one case of tachycardia in a patient with a double deletion in the TRβ gene has been described (Takeda et al., J. Clin. Endocrinol. And Metab. 1992, vol. 74, p. 49);

The double-knocked TRα gene (but not the β gene) in mice has a slow pulse compared to control mice;

western blotting of myocardial TRs shows the presence of TRα ₁ , TRα ₂ and TRβ ₂ proteins, but not TRβ ₁ .

If these signs are correct, then the TR β-selective agonist can be used to imitate a number of actions of the thyroid hormone, although it has a weaker effect on the heart. Such a compound can be used in (1) replacement therapy in elderly people with hypothyroidism with an increased risk of cardiovascular complications; (2) replacement therapy in the elderly with asymptomatic hypothyroidism with an increased risk of cardiovascular complications; (3) obesity; (4) cholesterolemia caused by increased plasma LDL levels; (5) depression; (6) osteoporosis in combination with a bone resorption inhibitor.

In accordance with this invention created compounds representing ligands of thyroid receptors and having the General formula

Where

X is oxygen (—O—);

Y is - (CH ₂ ) _n -, where n is an integer from 1 to 3, or —C = C—, which is a cis or trans isomer;

R ₁ alkyl containing 3-6 carbon atoms;

R ₂ and R _{3 are the} same or different and represent hydrogen, halogen, alkyl containing 1-4 carbon atoms, while at least one of R ₂ and R ₃ does not represent hydrogen;

R ₄ is hydrogen or lower alkyl;

R ₅ is hydrogen;

R ₆ is a carboxylic acid or its ester;

R ₇ is hydrogen;

including all stereoisomers thereof or a pharmaceutically acceptable salt thereof.

In addition, an object of the present invention is a method for preventing, inhibiting or treating a disease caused by metabolic dysfunction or dependent on the expression of a T ₃ -regulated gene, in which the compound of formula I is administered in a therapeutically effective amount. The compound of formula I is preferably an agonist, preferably selective for the thyroid hormone beta receptor. Examples of such diseases caused by metabolic dysfunction or dependent on the expression of a T ₃ -regulated gene are presented below and include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmia, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, as well as glaucoma and congestive heart failure. .

The compounds of formula I can be in the form of salts, in particular in the form of pharmaceutically acceptable salts. If, for example, at least one basic center is present in the compound of formula I, they can form acid addition salts. These salts are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or hydrohalic acid, with strong carboxylic acids, such as alkane carboxylic acids with 1-4 carbon atoms, unsubstituted or substituted, for example, with halogen for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids s, for example, ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids (e.g., aspartic acid, or lysine, or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4) - alkyl or arylsulfonic acids unsubstituted or substituted, for example, with halogen, for example methanesulfonic acid or p-toluenesulfonic acid. Also, if required, the corresponding acid addition salts having an additional center of basicity can be obtained. Compounds of formula I containing at least one acid group (e.g., COOH) can also form salts with bases. Suitable base salts are, for example, metal salts, such as alkali metal salts or alkaline earth metal salts, for example, sodium, potassium or magnesium salts, or ammonium salts or salts with organic amines, such as morpholine, thiomorpholine, piperidine, pyrrolidine, mono -, di- and tri-lower alkyl amines, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethylpropylamine, di- or trihydroxy lower alkylamine, for example mono-, di-, or triethanolamine. In addition, corresponding internal salts may form.

Preferred salts of compounds of formula I that contain a basic group include monohydrochloride, hydrosulfate, methanesulfonate, phosphate or nitrate.

Preferred salts of compounds of formula I that contain an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amine salts.

Preferred are compounds of formula I, where

X is O;

Y is cis or trans ethylene;

R ₁ is isopropyl;

R ₂ and R ₃ independently mean independently bromo, chloro or methyl;

R ₄ is hydrogen or methyl;

R ₅ is hydrogen;

R ₆ is carboxyl;

R ₇ is hydrogen.

Other preferred compounds are compounds of formula I in which X is O;

Y is - (CH ₂ ) _n -, where n is 1 or 2;

R ₁ denotes alkyl containing 1-3 carbon atoms;

R ₂ and R ₃ are independently bromo, chloro or methyl;

R ₄ is hydrogen or methyl;

R ₅ is hydrogen;

R ₆ carboxyl;

R ₇ is hydrogen.

Most preferred are compounds of formula I according to the invention in which X is O;

Y is - (CH ₂ ) _n -, where n is 1;

R ₁ denotes alkyl containing 1-3 carbon atoms;

R ₂ and R _{3 are} independently bromo or chloro;

R ₄ is hydrogen or methyl;

R ₅ is hydrogen;

R ₆ is carboxyl;

R ₇ is hydrogen.

Therefore, preferred compounds of the invention will have the structure

or

Preferred compounds have the following structure:

or

The most preferred compounds of the invention are structured

or

Compounds of formula I can be prepared by methods, examples of which are shown in the reaction schemes below, as well as by relevant methods published in the literature, which are used by those skilled in the art. Examples of reagents and methods for carrying out these reactions are presented below and in the Examples section. The protection and deprotection in the Schemes below may be carried out by methods well izvestnmi in the art (see., E.g., TWGreen and PGMWuts, «Protecting Groups in Organic Synthesis», 3 ^rd Edition, Wiley, 1999).

Scheme 1 shows a general synthetic approach to the compounds of formula I, where X = O, which uses the addition of the corresponding substituted iodonium salt 1 to the corresponding phenol 2 to form intermediate 3. In formula 1 and in all the attached formulas contained in the schemes described below, PG (MH) refers to a protective group for this functional group (in this example, for phenolic oxygen). The specific protecting groups for each particular intermediate are well known to those skilled in the art (see also the Protecting Groups in Organic Synthesis link above). Appropriate manipulation of the protective and functional groups gives the desired compound of formula I. For example, intermediate 2 can be nitrophenol (R 'and R''are oxygen) and the resulting addition product is the corresponding nitro derivative of diaryl ether 3, where R' = R '' = O. This intermediate nitro compound can be easily reduced to the corresponding arylamine (see discussion below). The resulting arylamine can then be easily acylated to produce the desired compounds of formula I (X = O). Intermediate 2 may also be a compound with a protected amino group, for example R ′ = R ⁵ and R ″ = PG. The protecting group (PG, 3G) may be a carbamate group such as tert-butyloxycarbonyl (BOC) or benzyloxycarbonyl (CBZ), which can later be removed by acidolysis and / or hydrogenolysis under standard conditions. Acylation of the resulting arylamine also by methods well known to those skilled in the art will produce the desired compounds of formula I. In addition, the arylamine (intermediate 3, where R '= R "= H), formed upon reduction of the coupling product, a nitrobenzene analogue, can react with the aldehyde by reductive amination reaction, thus aldehyde moiety of the group R ₅ is introduced. Methods for reductive amination, e.g., with sodium cyanoborohydride or sodium triacetoxyborohydride, are well keV stnye skilled in the art. The resulting product can then be acylated by conventional means to give compounds of formula I.

Scheme 1

The method using the iodonium salt illustrated by Scheme 1 is described in detail in the literature on the synthesis of thyroid hormone analogs (Novel Thyroid Receptor Ligands and Methods, Y.-L. Li, Y. Liu, A. Headfors, J. Malm, C. Mellin, M. Zhang, International Application WO 9900353 Fl 990107; DMB Hickey et al., J. Chem. Soc. Perkin Trans. I, 3103-3111, 1988; N. Yokoyama et al., J. Med. Chem., 38, 695-707, 1995) and for diaryl esters in general (EACouladouros, VI Moutsos, Tetrahedron Lett., 40, 7023-7026, 1999).

Scheme 2 shows another synthetic approach to the compounds of formula I, where X = O, in which the corresponding substituted nitrobenzene intermediate 5 is alkylated with the corresponding substituted phenol 4 to give nitrointermediate 6. The nitro group in intermediate 6 can be reduced to the amino group by methods well known in the art, such as catalytic hydrogenation in the presence of, for example, Raney nickel or palladium on carbon in a polar solvent such as glacial acetic acid or ethanol. Alternatively, reduction can be carried out using iron powder in dilute acetic acid at room temperature. Appropriate manipulations with the protective and functional groups give the desired compounds of formula I.

Scheme 2

Этот способ, иллюстрированный на Схеме 2 как общий метод синтеза, хорошо описан в литературе (P.D.Leeson, J.C.Emmet, J.Chem. Perkm Trans. 1,3085-3096,1988; N.Yokoyama et al., J. Med., 38, 695-707, 1995).

This method, illustrated in Scheme 2 as a general synthesis method, is well described in the literature (PDLeeson, JCEmmet, J.Chem. Perkm Trans. 1.3085-3096.1988; N. Yokoyama et al., J. Med., 38, 695-707, 1995).

Other methods for the synthesis of compounds of formula I, where X = O, NH, S, CO or CH ₂ are generally described in the literature (X = O: DMB Hickey et al., J. Chem. Soc. Perkin Trans. I, 3097-3102 , 1988; Z.-W. Guo et al., J. Org. Chem., J. Org. Chem., 62, 6700-6701, 1997; DMT Chan et al., Tetrahedron Lett., 39, 2933-2936 , 1998; DAEvans et al., Tetrahedron Lett., 39.2937-2940, 1998; GMSalamonczyk et al., Tetrahedron Lett., 38, 6965-6968, 1997; JF Marcoux, J. Am. Chem. Soc., 119, 10539-10540; AVKalinin et al., J. Org. Chem., 64, 2986-2987, 1999; X = N: DMT Chan et al., Tetrahedron Lett., 39, 2933-2936, 1998; JPWolfe et al. , J. Am. Chem. Soc., 118, 7215, 1996; MS Driver, JF Hartwig, J. Am. Chem. Soc., 118, 7217, 1996; see references in CG Frost, P. Mendonca, J. Chem Soc. Perkin I, 2615-2623, 1998; for X = S: CR Harrington, Biochem. J., 434-437, 1948; A. Dibbo et al., J. Chem. Soc., 2890-2902, 1961 ; N. Yokoyama et al., Patent USA 54017726, 1995; X = CO or CH: L. Homer, HHG Medem, Chem. Ber., 85, 520-530, 1952; G. Chiellini et al., Chemistry and Biology, 5, 299-306, 1988) .

Methods of synthesizing compounds of formula I in which X = O, a R ₂ and R ₃ independently vary, taking the meanings: hydrogen, halogen and alkyl, are described in Novel Thyroid Receptor Ligands and Methods, Y.-L. Li, Y. Liu, A. Hedfors, J. Malm, C. Mellin, M. Zhang, International Application WO 9900353 A1 990107.

Another general method for the synthesis of compounds of formula I in which X = O is shown in Scheme 3. By this method, the corresponding substituted iodonium salt 1 is attached to the corresponding intermediate 7, a substituted 4-hydroxybenzoic acid. The carboxy protecting group (PG ′) in the resulting addition product 8 is then removed. The resulting intermediate free carboxylic acid then undergoes Curtius rearrangement in the presence of known reagents such as diphenylphosphoryl azide (DPPA). Intermediates formed during the Curtius rearrangement can be trapped either with tert-butanol or benzyl alcohol to give product 9, aniline with a protective, tert-butoxycarbonyl (BOC) or benzyloxycarbonyl (CBZ) group, respectively. These protecting groups can be removed by methods well known in the art to give the corresponding free amino group. The amine can then be acylated to form compounds of formula I with X = O by any of the well-known methods, for example by acylation with a free carboxylic acid in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) or (-1- [3- (dimethylamino) propyl] -3 ethyl carbodiimide (EDCI).

Alternatively, the free amine can be acylated with a carboxylic acid derivative in the presence of an equivalent amount of a tertiary amine such as triethylamine or N-methylmorpholine.

Scheme 3

All stereoisomers of the compounds of this invention are contemplated either as a mixture or in pure or substantially pure form. The compounds of this invention may have asymmetric centers at any carbon atom, including any of the atoms of the substituents R. Therefore, the compounds of formula I can exist as enantiomers, or stereomers, or as mixtures thereof. In the production process, racemates, enantiomers or stereoisomers can be used as starting materials. When diastereomeric or enantiomeric products are obtained, they can be separated by appropriate methods, for example, chromatography or fractional crystallization.

The compounds of the invention are agonists that are preferably selective for the thyroid hormone beta receptor and as such are useful in treating obesity, hypercholesterolemia and atherosclerosis by lowering serum LDL levels, alone or in combination with a lipid modulating drug, such as an HMG-inhibitor CoA reductase, fibrate, MTP inhibitor, squalene synthetase inhibitor and / or other lipid-lowering agent, and / or, if necessary, in combination with an antidiabetic agent; suitable for reducing depression, alone or in combination with an antidepressant such as fluoxetine and desipramine; and are useful for stimulating bone formation in the treatment of osteoporosis, alone or in combination with any known bone resorption inhibitor such as sodium alendronate. In addition, the compounds of the invention can be used as replacement therapy in elderly patients with hypothyroidism or asymptomatic hypothyroidism with an increased risk of cardiovascular complications, in the treatment of the elderly to give them a sense of health and in the treatment of non-toxic goiter, in the treatment of palillary or follicular thyroid cancer glands (alone or with T4), in the treatment of skin lesions such as psoriasis, glaucoma, cardiovascular diseases, for example for the prevention or treatment of atherosclerosis and stasis heart failure.

The compounds of the invention can be used alone or in combination with appetite suppressants, such as sibutramine, and / or in combination with anti-obesity drugs, and / or in combination with a β3 agonist to treat obesity.

The compounds of the invention can also be used to treat skin lesions or diseases accompanied by dermal atrophy, including the cure of dermal atrophy caused by local glucocorticoids, including the “restoration” of dermal atrophy caused by local glucocorticoids, the prevention of dermal atrophy, local glucocorticoids (for example, with simultaneous treatment with local glucocorticoid or pharmacological product containing a glucocorticoid and a compound of the invention), reconstitution / warning dermal atrophy caused by systemic treatment with glucocorticoids, restoration / prevention of respiratory system atrophy caused by topical use of glucocorticoids, UV-induced dermal atrophy or dermal atrophy associated with aging (wrinkles, etc.), healing of wounds, keloid, atrophied skin strips, cellulite, bumpy skin, photochemical skin damage, lichen planus, ichthyosis, acne, treatment of psoriasis, Dernier disease, eczema, diffuse neurodermatitis, chloracne, pitiriasis and skin scars.

In the treatment of skin lesions and diseases described above, the compounds of the invention can be used alone or in combination with retinoids, such as tretinoin or an analogue of vitamin D in the amounts prescribed by the PDR (medical reference book).

The lipid-lowering agent, which, if necessary, can be used in combination with the compounds of formula I according to the invention, may include thiazolidinediones, MTP inhibitors, HMG CoA reductase inhibitors, squalene synthetase inhibitors, fibrin acid derivatives, ACAT inhibitors, cholesterol absorption inhibitors, cotransporter inhibitors ⁺ Na ⁺ bile acid in the ileum, substances that enhance the excretion of bile acids, and / or nicotinic acid and its derivatives.

The MTP inhibitors used herein include those disclosed in US Pat. Nos. 5,595,872, 5,739,135, 5,712,279, 5,760,246, 5,827,875, 5,885,983 and 5,962,440. Each of the preferred inhibitors described in each of the above patents is preferred.

The most preferred MTP inhibitors used in this invention include the preferred MTP inhibitors described in US patents 5739135 and 5712279 and 5760246.

The most preferred inhibitor is

9- [4- [4 - [[2- (2,2,2-Trifluoroethoxy) benzoyl] amino] -1-piperidinyl] boogyl] -N- (2,2,2-trifluoroethyl) -9H-fluorene-9 carboxamide

The lipid-lowering agent may be an inhibitor of HMG CoA reductase, which includes, without limitation, mevastatin and related compounds described in US patent 3983140, lovastatin (mevinolin) and related compounds described in US patent 4231938, pravastatin and related compounds described, for example, in US patent 4346227, simvastatin and related compounds described in US patent 4448484 and 4450171. Other inhibitors of HMG CoA reductase that can be used according to this invention include, but are not limited to fluvastatin, described in US Pat. No. 5,354,772, cerivastatin disclosed in US Pat. Nos. 5,006,530 and 5,171,080, atorvastatin disclosed in US Pat. WO 86/03488, 6- [2- (substituted-pyrrol-1-yl) -alkyl) pyran-2-ones and their derivatives, disclosed in US Pat. No. 4,647,576, dichloroacetate of compound SC-45355 from Searle (3-substituted pentanedio derivative acids), imidazole analogues of mevalonolactone disclosed in international WO 86/07054, 3-carboxy-2-hydroxypropanephosphonic acid derivatives disclosed in French Patent 2,596,393, 2,3-disubstituted pyrrole, furan and thiophene derivatives disclosed in European Patent Application 0221025, naphthyl analogues of mevalonolactone disclosed in US Pat. No. 4,686,237 , octahydronaphthalenes, such as those disclosed in US Pat. No. 4,499,289, keto analogs of mevinolin (lovastatin), disclosed in European Patent Application 0142146 A2, as well as other known HMG CoA reductase inhibitors.

In addition, phosphinic acids useful for the inhibition of HMG CoA reductase suitable for use in the invention are described in English patent GB 2205837.

Squalene synthetase inhibitors suitable for use in this invention include, but are not limited to, the α-phosphonosulfonates disclosed in US Pat. No. 5,712,396, the phosphonosulfonates described by Biller et al., J. Med. Chem., 1988, vol., 31, No. 10, pp. 1869-1871, including isoprenoid (phosphinylmethyl) phosphonates and other squalene synthetase inhibitors disclosed in US Pat. Nos. 4,871 and 4,924,024 and in Biller, SA, Neuenschwander, K ., Ponpipom, MM, and Poulter, CD, Current Pharmaceutical Design, 2, 1-40 (1996).

In addition, other squalene synthetase inhibitors suitable for use in this invention include terpenoid pyrophosphates disclosed by P. Ortiz de Montellano et. al., J. Med. Chem., 1977, 20, 243-249, Farnesyl diphosphate analog A and presquale pyrophosphate analogs (PSQ-PP), disclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293, phosphinylphosphonates, as reported by McClard, R.W. et al., J. A. S. S., 1987, 109, 5544, and cyclopropanes described by Capson, T.L., Ph. D dissertation, June, 1987, Dept. Med. Chem. U of Uta, Abstract, Table of Contents, pp. 16, 17, 40-43, 48-51, Summary.

Other lipid-lowering agents suitable for use in this invention include, but are not limited to, fibrinic acid derivatives such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol and related compounds described in US Pat. No. 3,674,836, moreover, probucol and gemfibrozil are preferred, substances that enhance the excretion of bile acids, such as cholestyramine, colestipol and DEAE-Sephadex (Secholex ^® , Policexide ^® ), as well as lipostabil (Rhone-Poulenc), Eisai e-5050 (a derivative of substituted ethanolamine) , imanixil (НОЕ-402), tetrahydrolipstatin (THL), istigmastanylphosphorylcholine (SPC, Roche), aminocyclodextrin (Tanabe Seiyoku), Ajinomoto AJ-814 (azulene derivative), melamine (Sumitomo), CLoz 27-082-035-082 -283546 from American Cyanamid (derivatives of disubstituted urea), nicotinic acid, acipimox, acifran, neomycin, p-aminosalicylic acid, aspirin, poly (diallylmethylamine) derivatives, such as the poly (dialyldimethyldryl) quaternary ammonium salt of ammonium base ionones, such as those disclosed in US Pat. No. 4,027,009, and other known ve EU ETS, reduce serum cholesterol.

Another lipid-lowering agent may be an ACAT inhibitor, such as described in Drugs in Future 24, 9-15 (1999), (Avasimbe); "The ACAT inhibitor. Cl-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters ”, Nicolosi et al., Atherosclerosis (Shannon, Irel). (1998), 137 (1), 77-85; "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hipolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB100-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc. Drug Rev. (1998), 16 (1), 16-30; "RP 73163: a bioavailable alkylsulfinyl-diphenylimidazole ACAT inhibitor." Smith, C., et al., Bioorg. Med. Chem. Lett. (1996), 6 (1), 47-50; "ACAT inhibitors: physiological mechanisms for hypolipidemic and anti-atherosclerotic activities in experimental animals", Krause et al., Editor (s) "Ruffolo, Robert R., Jr .; Hollinger, Mannfred A., Inflammation: Mediators P (1995) , 173-98, Publisher: CRC, Boca Raton, Fla .; "ACAT inhibitors: potential anti-atherosclerotic agents", Slivcovic et al., Curr. Med. Chem. (1994), 1 (3), 204-25; "Inhibitors of acyl-CoA: cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. 6. The first water-soluble ACAT inhibitor with lipid-regulating activity. Inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N '- [(1-phenylcyclopentyl) methyl] ureas with enhanced hypocholesterolemic activity ”, Stout et al., Chemtracts; Org. Chem. (1995), 8 (6), 359-62.

The lipid-lowering agent may be an absorption (absorption) inhibitor, preferably SCH48461 from Schering-Plow, as well as an adsorption inhibitor disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).

The lipid-lowering agent may be an inhibitor of the ileum Na ⁺ / bile acid cotransporter, such as described in Drugs of the Future, 24, 425-430 (1999).

Preferred hapolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin.

The compounds of formula I according to the invention are used with a lipid-lowering agent, an antidepressant and / or an inhibitor of bone resorption, and / or an appetite suppressant (if any), in a weight ratio of about 500: 1 to 0.005: 1, preferably about 300: 1-0 01: 1.

An antidiabetic agent, which, if necessary, is used in combination with the compounds of formula I according to the invention, may include biguanides, sulfonylureas, glucosidase inhibitors, thiazolidinediones and / or aP2 inhibitors and / or PPARα agonists, PPARγ agonists or double α / γ agonists, and / or SGLT inhibitors or meglitinide.

The antidiabetic agent may be an oral antihyperglycemic agent, preferably a biguanide, such as metformin or phenformin or their salts.

If the antidiabetic agent is biguanide, the compounds of formula I are used in a weight ratio of biguanide of about 0.01: 1-100: 1, preferably about 0.05: 1-2: 1.

The antidiabetic agent may also preferably be a sulfonylurea, such as gliburide (also known as glibenclamide), gliperimide (described in US Pat. -cells, with glyburide and glipizide being preferred.

The compounds of formula I are used in a weight ratio with urea of about 0.01: 1-100: 1, preferably about 0.2: 1-10: 1.

The compounds of formula I are used with sulfonylurea in a weight ratio of about 0.2: 1-10: 1.

The oral antidiabetic agent may also be a glucosidase inhibitor, such as acarbose (described in US Pat. No. 4,639,436), which can be taken in a separate dosage form.

The compounds of formula I can be used with a glucosidase inhibitor in a weight ratio of about 0.01: 1-100: 1, preferably about 0.5: 1-50: 1.

Compounds of formula I may be used in combination with a thiazolidinedione oral antidiabetic agent or other insulin sensitizers (which affect insulin sensitivity in patients with NIDDM), such as troglitazone (Rezulin ^® Warner-Lambert company, described in U.S. Patent No. 4,572,912), rosiglitazone (SKB) , proglitazone (Takeda), Mitsubishi MCC-555 (described in US Pat. No. 5,594,016), Glaxo-Welcome GI-262570, eglitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer).

The compounds of formula I can be used with thiazolidinedione in a weight ratio of about 0.01: 1-100: 1, preferably about 0.5: 1-5: 1.

Sulfonylurea and thiazolidinedione in amounts of less than about 150 mg of an oral antidiabetic agent can be used as a single tablet with compounds of formula I.

The compounds of formula I can also be used in combination with a non-oral antihyperglycemic agent, such as insulin, or with a glucagon-like peptide - 1 (GLP-1), such as GLP-1 (1-36) amide, GLP-1 (7-36) amide , GLP-1 (7-37) (described in US Pat. No. 5,614,492, which can be administered by injection intranasally or using transdermal or buccal devices.

Metformin, sulfonylureas such as glyburide, glimepiride, glypiride, glipizide, chlorpropamide and glyclazide and acarbose glucosidase inhibitors, or maglitol, or insulin, if present, can be used in the preparations as described above and in the amounts and doses indicated by the physician reference books.

Metformin or its salt, if present, can be used in amounts of about 500-2000 mg per day, and can be administered in a single dose or in divided doses one to four times a day.

The thiazolidinedione antidiabetic agent, if present, can be used in amounts of about 0.01-2000 mg / day, and can be administered in single or divided doses one to four times a day.

If insulin is present, then it is used in the preparations, amounts and doses indicated in the medical reference books.

If present, GLP-1 peptides can be administered as oral buccal preparations nasally or parenterally, as described in US Pat. Nos. 5,346,701.5614492 and 5631224.

The antidiabetic agent may also be an α / γ double PPAR agonist, such as described by Murakami et al., “A Novel Insulin Sensitizer Acts as a Coligand for Peroxisome Proliferation - Activated Receptor Alpha (PPAR alpha) and PPAR gamma. Effect on PPAR alpha Activation on Abnormal Lipid Metabolism in Liver of Zucker Fatty Rats ", Diabets 476 1841-1847.

The antidiabetic agent may be an aP2 inhibitor, such as described in US patent application 09/391053, filed September 7, 1999, and in provisional patent application US 60/127745, filed April 5, 1999, and is used in the doses indicated in this description .

The antidiabetic agent may be an SGTL2 inhibitor, such as described in provisional patent application US 60/158773, filed October 12, 1999.

The compounds of formula I are used in a weight ratio with a PPARα agonist, a PPARγ agonist, a PPARα / γ double agonist, an SGTL2 inhibitor and / or an aP2 inhibitor of about 0.01: 1-100: 1, preferably about 0.5: 1 -5: 1.

The prescribed doses should be precisely adjusted in accordance with the age, body weight and condition of the patient, as well as in accordance with the method of administration, dosage form and schedule and the desired result.

Dosages and formulations of the lipid-lowering agent and antidiabetic agent are described in many patents and patent applications discussed above, and in PDR (NVS).

Dosages and formulations used for another hypolipidemic agent, an antidepressant, an inhibitor of bone resorption, an appetite suppressant, and an anti-obesity agent, where required, are taken from medical reference books.

In the case of oral administration, satisfactory results can be obtained by using an MTP inhibitor in an amount of about 0.01-100 mg / kg and preferably about 0.1-75 mg / kg once to four times a day.

A preferred oral dosage form, such as tablets or capsules, contains an MTP inhibitor in an amount of about 1-500 mg, preferably about 2-400 mg, and more preferably about 5-250 mg, one to four times a day.

For parenteral administration, an MTP inhibitor can be used in an amount of about 0.005-10 mg / kg, and preferably about 0.005-8 mg / kg, one to four times a day.

For oral administration, a satisfactory result can be obtained by using an HMG CoA reductase inhibitor, for example pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin or cerivastatin, for example, in an amount of about 1-2000 mg and preferably about 4-200 mg.

A squalene synthetase inhibitor can be used in dosages of about 10-2000 mg, and preferably about 25-200 mg.

A preferred oral dosage form, for example tablets or capsules, contains an HMG CoA reductase inhibitor in an amount of about 0.1-100 mg, preferably about 5-80 mg, and more preferably about 10-40 mg.

A preferred oral dosage form, such as tablets or capsules, contains a squalene synthetase inhibitor in an amount of about 10-500 mg, preferably about 25-200 mg.

The compounds of formula I and a lipid-lowering agent, an antidepressant or an inhibitor of bone resorption can be used together in the same oral dosage form or in separate oral dosage forms taken simultaneously.

The above compositions may be administered in dosage forms as described above, in a single dose or in divided doses, one to four times a day. You can advise the patient to start with a combination of low doses and gradually switch to a combination of high doses.

A preferred lipid-lowering agent is pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin or cerivastatin.

The compounds of formula I according to the invention can be administered orally or parenterally, for example subcutaneously or intravenously, as well as nasally, rectally or sublingually to various types of mammals that are known to be susceptible to such diseases, for example, humans, cats, dogs and the like, in the amount of about 0.1-100 mg / kg, preferably about 0.2-50 mg / kg and more preferably about 0.5-25 mg / kg (or about 1-2500 mg, preferably about 5-2000 mg) according to the scheme in the form of a single dose or 2-4 separate daily doses.

The active substance can be used in compositions such as a tablet, capsule, ointment, hydrophilic ointment, cream, lotion, solution or suspension, or in carriers of another kind, such as transdermal devices, electrophoresis devices, rectal suppositories, inhalation devices, etc. . The composition or carrier may contain about 5-500 mg of the compound of formula I per unit dose. They can be mixed appropriately with a physiologically acceptable excipient or carrier, excipient, binder, preservative, stabilizing agent and flavoring agent in accordance with accepted pharmaceutical practice.

The following working examples represent preferred embodiments of the present invention.

Example 1

3 - [[3,5-dibromo- [4-hydroxy-3- (1-methylethyl) phenoxy] phenyl] amino] -3-oxopropanoic acid

Compound 1a

Bis (3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate (32.8 g, 64 mmol), 2,6-dibromo-4-nitrophenol (12.6 g, 42 mmol) and Cu powder [Lancaster, 300 mesh (6, 8 g, 108 mmol)] are suspended in 400 ml of CH ₂ Cl ₂ in a flask coated with aluminum foil. While boiling, triethylamine is added and the reaction mixture is stirred under argon in the dark for 4 days. The crude reaction mixture was evaporated to about 70 ml and then chromatographed in two portions, 1.8 liters each, of Merk silica gel with a 3-5% solution of ethyl acetate in hexanes. The total yield of the compound is 15.4 g (81.9%).

Compound 1b

Compound 1a (15.2 g, 34.15 mmol) was dissolved in 129 ml of glacial acetic acid and 13 ml of water. Iron powder (Aldrich <10 microns, 12 g, 215 mmol) was added and the reaction mixture was stirred under argon overnight. The reaction mixture was filtered through a pad of celite and the celite washed with 50 ml of acetic acid. The filtrate was evaporated to approximately 60 ml and poured into 400 g of Na ₂ CO ₃ . Water (400 ml) was added and the product was extracted with ethyl acetate (3 × 500 ml each portion). Ethyl acetate was evaporated in vacuo and the residue (13.2 g was chromatographed on 1.8 liters of Merk silica gel with ethyl acetate: hexane 8: 2. Compound 1b (8.75 g) was obtained in 61.7% yield as a solid. Proton and carbon NMR spectra correspond to a given structure.

Compound 1c

Compound 1b (8.1 g, 19.7 mmol) was dissolved in 20 ml of methylene chloride and this solution was added dropwise to a pre-cooled (about -60 ° C) solution of BBr ₃ (18 ml, about 10 equivalents) of methylene chloride under argon . At this low temperature, a solid precipitates. The mixture slowly reaches 0 ° and then stirred for one hour at this temperature. The reaction mixture was diluted with 200 ml of CH ₂ Cl ₂ and quenched by pouring into a cold, vigorously stirred saturated aqueous solution of Na ₂ CO ₃ and CH ₂ Cl ₂ (300 ml). The organic layer was separated, diluted with 100 ml of MeOH and evaporated in vacuo, dissolved in MeOH (100 ml) and evaporated again three times. The residue was dissolved in 400 ml EtOAc, washed with 2X saturated NaHCO ₃ solution, brine, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give 1c as a solid (7.2 g, 91% yield). Proton and carbon NMR spectra correspond to a given structure.

Compound 1d

Compound 1c (6.23 g, 15.5 mmol), monoethyl malonic ester (2.9 g, 22 mmol), N-methylmorpholine (1.75 ml, 15.8 mmol) and gpdroxy-7-azabenzotriazole (3.1 g, 23 mmol) is partially dissolved in 200 ml of CH ₂ Cl ₂ . This reaction mixture was cooled to 0 ° and (1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (4.4 g, 23 mmol) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with 200 ml of CH ₂ Cl ₂ and washed with water, saturated aqueous NaHCO ₃ solution, brine, dried Na ₂ SO ₄ , filtered and evaporated. The crude product was chromatographed in two batches on 300 g Merk silica gel each with 30% ethyl acetate in hexanes. The intermediate fractions were combined and evaporated to give 5.3 g (66.7%) of pure product The first and last fractions are combined, from which they are obtained 0.96 g of product Id containing the starting malonate and an unknown impurity.

Example 1

Malonic ester 1d (5.180 g, 9.91 mmol) was dissolved in 29.5 ml of methanol and cooled to 0 °. Then, after 5 minutes, 1N sodium hydroxide (29.73 mmol, 3 equiv.) Was added to the reaction mixture, and the reaction mixture was brought to room temperature. After 15 minutes, methanol was removed in vacuo. Then the remaining alkaline solution is diluted with 29.7 ml of water and cooled in an ice bath. 1N hydrochloric acid was added dropwise to the main solution until a pH of 1 was obtained. The resulting white "semi-solid" substance was collected in a large funnel with a glass filter. The solid is washed 5 times with cold water, then dried for 3 days with potassium hydroxide in vacuo. The final weight of the title compound is 5.01 g (99% yield). The mass spectrum corresponds to a given structure.

¹ NMR (500 MHz, acetone - D6, δ): 8.07 (s, 2H), 6.75 (m, 2H), 6.37 (dd, 1H, J = 8.8.3.3 Hz) 3.51 (s, 2H); 3.28 (q, 1H; J = 6.5 Hz); 1.17 (d, 6H; J = 7.1 gHz).

¹³ C NMR (500 MHz, methanol D3, δ): 171.06; 167.36; 151.54; 150.59; 147.15; 138.30; 137.47; 125.04; 119.54; 116.34; 114.14; 113.14; 41.98; 28.15; 22.80.

Elemental analysis corresponds to the formula C ₁₈ H ₁₇ Br ₂ NO ₅ . 1.75 H ₂ O: C, 41.68%; H, 3.89%; N, 2.63%; Br, 30.70%.

Example 2

3 - [[3,5-dichloro- [4-hydroxy-3- (1-methylethyl) phenoxy] phenylallylamino] -3-oxopropanoic acid.

Compound 2a

Bis (3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate (15.0 g, 29.4 mmol), 2,6-dichloro-4-nitrophenol (4.16 g, 20 mmol) and Cu powder [Lancaster 300 mesh (3.2 g, 50 mmol) are suspended in 200 ml of CH ₂ Cl ₂ in a flask coated with aluminum foil. With stirring, triethylamine (8.4 ml, 100 mmol) was added and the reaction mixture was stirred under argon in the dark for 5 days. The crude reaction mixture was evaporated to about 50 ml, and then chromatographed over a pad of Merk silica gel, 2 L, 3% ethyl acetate in hexanes. The total yield of compound 2a is 4.9 g (68.8%). The proton NMR spectrum corresponds to the structure of the compound.

Compound 2b

Compound 2a (4.9 g, 13.8 mmol) was dissolved in 80 ml of glacial acetic acid and 8 ml of water. Iron powder (Aldrich <10 microns, 4.6 g, 81.6 ml) was added and the reaction mixture was stirred under argon overnight. The reaction mixture was filtered through celite and the celite pad was washed with 50 ml of methanol. The filtrate was evaporated in vacuo. A saturated solution of Na ₂ CO ₃ (400 ml) was added and the product was extracted with ethyl acetate (3X 500 ml each). The ethyl acetate extracts were evaporated in vacuo and the residue was chromatographed over 1.8 L of Merk silica gel with ethyl acetate: hexanes (8: 2). Compound 2b (2.2 g) was obtained in 49.9% yield as a solid. Proton and carbon NMR spectra confirm the desired structure.

Compound 2c

Compound 2b (1.8 g, 5.65 mmol) was dissolved in 15 ml of methylene chloride and this solution was added under argon dropwise to a pre-cooled (about -60 °) BBr ₃ solution (5.3 ml, 56.5 mmol) in 40 ml of methylene chloride. At this low temperature, a solid precipitates. The reaction mixture is slowly heated to 0 ° and stirred at this temperature for one hour. The reaction mixture was diluted with 200 ml of CH ₂ Cl ₂ and quenched by pouring into a cold vigorously stirred mixture of a saturated aqueous solution of Na ₂ CO ₃ (200 ml) and CH ₂ Cl ₂ (200 ml). The organic layer was separated, diluted with 100 ml of MeOH and evaporated in vacuo and 3X from MeOH (50 ml each). The residue was dissolved in 300 ml EtOAc, washed with 2X saturated NaHCO ₃ , brine, dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give compound 2c as a solid (1.77 g, 99% yield). Proton and carbon NMR spectra confirm the desired structure.

Compound 2d

To a mixture of compound 2c (700 mg, 2.24 mmol), monoethyl malonate (440 mg, 3.32 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (632 mg, 3.33 mmol), 1-hydroxybenzotriazole (450 mg, 3.40 mmol) in CH ₂ Cl ₂ (24 ml), cooled in an ice bath, N-methylmorpholine (41 μl, 4.46 mmol) was added. Bring to room temperature and stirred under argon overnight (approximately 18 hours). The mixture was diluted with 30 ml of CH ₂ Cl ₂ and then washed successively with H ₂ O (3 × 100 ml), 1N HCl (3 × 150 ml), saturated NaHCO ₃ (3 × 120 ml) and brine (1 × 150 ml). The CH ₂ Cl ₂ layer was dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 632 mg of a white foamy substance. The crude product was purified by chromatography (75 g of silica gel, 20% EtOAc in hexane) to give 500 mg (52%) of purified compound 2d as a white substance. Proton and carbon NMR spectra and LC / MS confirm the structure of the product.

Example 2

To a solution of compound 2d (330 mg, 0.78 mmol) in methyl alcohol (3.9 ml) was added a 1N aqueous solution of sodium hydroxide (2.3 ml, 2.3 mmol). After 20 minutes, the mixture was evaporated in vacuo to an aqueous solution, which was diluted with 3.2 ml of distilled water. The solution was cooled to 0 ° and acidified by adding 1N HCl dropwise to pH 1. A white precipitate was collected and dried in vacuo over potassium hydroxide for 18 hours to obtain 288 mg (74%) of the title compound as a white solid. Proton and carbon NMR spectra and an LC / MS spectrum confirm the structure of a given product.

Example 3

3 - [[3,5-dichloro- [4-hydroxy-3- (1-methylethyl) phenoxy] -2-methylphenyl] amino] -3-oxopropanoic acid.

Compound 3a

To a solution of 4-amino-2,6-dichloro-3-methylphenol (0.70 g, 3.64 mmol) in anhydrous THF (18 ml) cooled in an ice bath was added trifluoroacetic anhydride (0.92 mg, 0 62 ml, 4.39 mmol). The mixture was brought to room temperature. After one hour, EtOAc (50 ml) was added to the mixture, and then washed with brine (2 × 25 ml). The EtOAc extract was dried over Na ₂ SO ₄ , filtered, evaporated and dried in vacuo to give 1.07 g of a crude product. The crude product was purified by chromatography (50 g of silica gel, 20% EtOAc in hexane) to give 0.93 mg (89%) of compound Za as a pale orange solid.

¹ H NMR (500 MHz, CD ₃ OD, δ) 7.22 (s, 1H), 2.22 (s, 3H)

LC - MS ESI ^- [M-H] ^- = 286, 288, 290 (100: 64:10)

Compound 3b

To a mixture of bis (3-isopropyl-4-methoxyphenyl) iodonium tetrafluoroborate (3.11 g, 6.07 mmol) and copper (0.31 g, 4.86 mmol) in CH ₂ Cl ₂ (12 ml) was added a solution of compound (0.70 g, 2.43 mmol) and triethylamine (0.49 g, 0.68 ml, 4.88 mmol) in CH ₂ Cl ₂ (12 ml). The mixture was stirred in the dark at room temperature under nitrogen for 92 hours. The mixture was filtered through a small pad of celite and the filtrate was evaporated in vacuo. The crude product was purified by chromatography (200 g of silica gel, 10% EtOAc in hexane) to give 0.42 g (40%) of compound 3b as a light orange solid.

¹ H NMR (500 MHz, CDCl ₃ , δ): 7.83 (s, 1H), 7.74 (br s, 1H), 6.86 (d, 1H, J = 2.6 Hz), 6.68 (d, 1H, J = 8.7 Hz), 6.4 (ds, 1H = 8.7, 3 Hz), 3.77 (s, 3H), 3.27 (M, 1H), 2.36 (s, 3H); 1.18 (d, 6H, 1 = 7 Hz).

LC- MS ESI ^- [M-H] ^- = 434, 436, 438 (100: 64: 10)

Compound 3c

An aqueous 48% HBr solution (5 ml) was added to a solution of compound 3b (243 mg, 0.557 mmol) in glacial acetic acid. The mixture is heated to 120 ° C and maintained at this temperature for 2 hours. The mixture was cooled to room temperature and then evaporated in vacuo. EtOAc (75 ml) was added to the residue, and then the pH was adjusted to 7 by adding an aqueous solution of NaHCO ₃ . The EtOAc layer was washed with brine (2 × 25 ml), dried (MgSO ₄ ), filtered, evaporated and dried in vacuo to give 179 mg of a violet solid crude product. The crude product was purified by chromatography (25 g of silica gel, 25% EtOAc in hexane) to give 117.2 mg (64%) of compound 3c as a white solid.

¹ H NMR (500 MHz, CD3OD, δ) 6.78 (s, 1H), 6.60 (d, 1H, J = 3.3 Hz) 6.58 (d, 1H, J = 8.8 Hz) 6.28 (dd, 1H, J = 8.8, 3.3 Hz); 3.21 (m, 1H); 1.14 (d, 6H, J = 6.6 Hz).

LC-MS ESI ^- [M-H] ^- = 324, 326, 328 (100: 64: 10)

3d connection

To a mixture of compound 3c (78 mg, 0.24 mmol), monoethyl malonate (47 mg, 0.36 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol), 1-hydroxybenzotriazole (48 mg, 0.36 mmol) in CH ₂ Cl ₂ (5 ml), cooled in an ice bath, N-methylmorpholine (25 mg, 27 μl, 0.24 mmol) was added. Bring to room temperature and stirred under N ₂ overnight (about 18 hours). The mixture was dissolved in EtOAC (50 ml) and then washed successively with H ₂ O (2 × 20 ml), 1N HCl (2 × 20 ml), saturated NaHCO ₃ solution (2 × 25 ml) and brine (2 × 25 ml) . The EtOAc layer was dried (MgSO ₄ ), filtered and evaporated in vacuo to give 136 mg of the crude product as a slightly pinkish thick oil. The crude product was purified by chromatography (25 g of silica gel, 30% EtOAc in hexane) to give 82 mg (78%) of compound 3d as a white solid.

¹ H NMR (500 MHz, CDCl ₃ , δ) 9.56 (s, 1H), 8.10 (s, 1H), 6.82 (d, 1H, J = 3.3 Hz), 6.60 ( d, 1H, J = 8.3 Hz), 6.34 (dd, 1H, J = 8.8; 2.8 Hz), 4.53 (s, 1H), 4.28 (q, 2H, J = 7.1 Hz), 3.53 (s, 2H), 3.15 (m, 1H), 2.38 (s, 3H), 1.34 (t, 3H, J 7.2 Hz), 1 , 22 (d, 6H, J = 6.6 Hz)

LC-MS ESI ^- [M-H] ^- = 438, 440, 442 (100: 64610)

Example 3

To a solution of compound 3d (70 mg, 0.16 mmol) in THF (1.5 ml) was added a 1N aqueous solution of lithium hydroxide (0.5 ml, 0.5 mmol). After one hour, the mixture was acidified with 1N HCl and then extracted with EtOAc (50 ml). The EtOAc extract was washed with brine (2 × 20 ml), dried (Na ₂ SO ₄ ), filtered and evaporated in vacuo to give 57 mg of a yellowish solid. The crude product contains traces of impurities, so it is cleaned by preparative reverse phase chromatography POPC [gradient solvent system, from 50% B: 50% A to 0% A: 100% B (A = 90% H ₂ O / 10% MeOH + 0 , 1% TFA, B = 90% MeOH / 10% H ₂ O + 0.1% TFA) in 10 minutes, YMC ODS 20 × 100 mm column] to obtain 40 mg (61%) of the title compound as a white solid .

¹ H NMR (500 MHz, CD ₃ OD, δ) 7.59 (s, 1H), 6.69 (d, 1H, J = 2.7 Hz), 6.60 (d, 1H, J = 8, 8 Hz), 6.30 (dts, 1H, J = 8.8; 3.3 Hz), 3.50 (s, 2H), 3.23 (m, 1H), 2.34 (s, 3H) 1.16 (d, 6H, J = 6.6 Hz)

MS ESI ^- = 410, 412, 414 (100: 64: 10)

Example 4

4 - [[3,5-dichloro- [4-hydroxy-3- (1-methylethyl) phenoxy] phenyl] amino] -4-oxobutanoic acid ..

Compound 4a

To a solution of compound 1c (50 mg, 0.125 mmol) pre-cooled to -78 ° C in CH ₂ Cl ₂ (500 μl), triethylamine (26 μl, 0.18 mmol) is added. Then 3-carbomethoxypropionyl chloride (16 μl, 0.14 mmol) was added dropwise. The reaction mixture was stirred for two hours. The solution was brought to room temperature and evaporated in vacuo to give 26 mg (yield 63%) of compound 4a as a yellow oil. The proton NMR spectrum and LC / MS correspond to the product with an admixture of diacelated by-product.

Example 4

To a solution of compound 4a (23 mg, 0.045 mmol) in methanol (1.5 ml) was added a 1N sodium hydroxide solution (0.08 ml, 0.08 mmol). After 3 hours, the mixture was evaporated in vacuo. The reaction mixture was cooled in an ice bath and 1N HCl was added until pH 1 was reached. The aqueous solution was extracted with ethyl acetate (3 × 30 ml). The combined ethyl acetate extracts were washed with brine and dried with Na ₂ SO ₄ . Evaporated in vacuo to give 15 mg of a white semi-liquid substance. The crude product is purified by preparative reverse phase chromatography (POP, HPLC) [gradient solvent system, from 50% A: 50% B to 0% a: 100% B (A = 90% H ₂ O / 10% MeOH + 0.1 % TFA, B = 90% MeOH / 10% H ₂ O + 0.1% TFA) for 15 minutes, YMC ODS column 20 × 100 mm] to give 8.0 mg (36%) of the title compound as a white solid . Proton NMR and LC / MS spectra correspond to a given product.

Example 5

5 - [[3,5-dichloro- [4-hydroxy- (1-methylethyl) phenoxy] phenyl] amino] -5-oxopentanoic acid

By the procedure described above in Example 4, 15 g (36% yield) of the title compound are obtained as a white solid. The proton NMR spectrum and the LC / MS spectrum correspond to a given structure.

Example 6

Compound 6a

To a mixture of compound 1c (40 mg, 0.10 mmol), maleic acid monomethyl ester (36 μl, 0.29 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (72 mg, 0.38 mmol), 1-hydroxybenzotriazole (54 mg, 0.40 mmol) in CH ₂ Cl ₂ (50 μl), cooled in an ice bath, triethylamine (46 μl, 0.028 mmol) was added. It is allowed to warm to room temperature and stirred under nitrogen overnight (about 18 hours). EtOAc (50 ml) was added and then washed successively with H ₂ O (2 × 20 ml), 1N HCl (2 × 20 ml), saturated NaHCO ₃ solution and brine (2 × 25 ml). The EtOAc layer was dried (Na ₂ SO ₄ ) and evaporated in vacuo to give 30 mg (58%) of the crude product as a light pink viscous oil. This product is allowed to enter the hydrolysis step. The proton NMR spectrum and the LC / MS spectrum correspond to a given product.

Example 6

To a solution of compound 6a (15 mg, 0.029 mmol) in methyl alcohol (1.5 ml) was added a 1N aqueous solution of sodium hydroxide (0.08 ml, 0.08 mmol). After 3 hours, the reaction mixture was evaporated in vacuo to remove methanol. The resulting solution was cooled in an ice bath and 1N HCl was added to pH 1. The aqueous solution was extracted with ethyl acetate (3 × 30 ml). The combined ethyl acetate extracts were washed with brine (2 × 30 ml) and dried over Na ₂ SO ₄ . The ethyl acetate extracts were evaporated in vacuo to give 12 mg of a white semi-liquid product. The crude product is purified by preparative reverse phase chromatography by POPC [gradient solvent system, from 50% A: 50% B to 0% A: 100% B (A = H ₂ O / 10% MeOH + 0.1% TFA, B = 90 % MeOH / 10% H ₂ O + 0.1% TFA) for 15 minutes, YMC ODS column 20 × 100 mm], 7.9 mg (53%) of the title compound are obtained as a white substance. The proton NMR spectrum and the LC / MS spectrum correspond to a given structure.

Example 7

By the method described in Example 6 above, 17.9 mg (46%) of the title compound are obtained as a white solid. The proton NMR spectrum and the LC / MS spectrum correspond to a given structure.

Examples 8-19

Using the appropriate methods described along with the methods described in "Novel Thyroid Receptor Ligands and Methods", Y.-L. Li., Y. Liu, A. Hedfors, J. Malm, C. Mellin, M. Zhang, International Application WO 9900353 A1, 990107, the compounds obtained in Examples 8-19 are described in the table below.

Example R2 R3 8 Me Me nine Me Br 10 Me Cl eleven Me I 12 Br Cl thirteen Br I 14 Cl I fifteen I I sixteen H Me 17 H Br eighteen H Cl nineteen H I

The table below shows the biological data for Examples 1,2 and 3 in the patent.

- in vitro evidence of thyroid hormone agonist activity:

- demonstration of strong receptor binding 150

- demonstration of high functional activity in cellular functional analysis;

- in vivo demonstration of metabolic effects:

- lowering cholesterol activity in the rat model shows the possibility of treating dyslipidemia, atherosclerosis, metabolic syndrome

- an increase in oxygen consumption demonstrates the ability to increase the metabolic rate and, therefore, to influence the reduction of body weight in the treatment of obesity

Table: Experiences Binding of TR-α, IC ₅₀ , (nM) ¹ Binding of TR-β, IC ₅₀ (nM) ² Function TR-α, EC ₅₀ (nM) ³ Function TR-β, EC ₅₀ (nM) ⁴ Decreased cholesterol ED ₅₀ (nmol / kg / day) ⁵ Increased oxygen consumption of ED ₅ (nmol / kg / day) one 0.29 0.024 9.9 2,5 16.9 75.1 2 0.7 0.04 32 7.3 <462 830 3 1,2 0.1 29th eleven <924 1180 ¹ Binding to a purified human thyroid hormone receptor alpha (TR-A), detectable radiolabelled L-thyronine (L-T3) substitution, IC ₅₀ indicates the concentration of the compound that causes 50% substitution of the radiolabeled ligand.
² Binding to the purified human thyroid hormone receptor alpha (TR-E), detectable substitution of the radiolabeled L-thyronine (L-T3),

IC ₅₀ denotes the concentration of the compound that causes 50% ligand substitution,
labeled with a radioactive label.
³ Functional activity determined by the analysis of transactivation in Chinese hamster ovary cells stably transfected using a full-sized human TR-a receptor using secreted
alkaline phosphatase as a control. EC ₅₀ denotes the concentration of the compound causing 50% of the maximum activity induced by L-thyronine (L-T3).
⁴ Functional activity as determined by transactivation analysis in Chinese hamster ovary cells stably transfected with the full-sized human TR-E receptor using secreted alkaline phosphatase as a control. EC ₅₀ denotes the concentration of the compound, causing 50% of the maximum activity induced by L-thyronine (L-T3).
⁵ Decrease in cholesterol activity is determined on the fed
Sprague-Dawley skinny rat cholesterol (males). After 2 weeks of feeding with cholesterol, the animals are given po (oral) carrier or in increasing doses one of the compounds for only 7 days, then (at this time) plasma cholesterol levels are determined. ED ₅₀ denotes the concentration of the compound, causing a decrease in cholesterol by 50% compared with the carrier.
⁶ An increase in metabolic rate (metabolism) is measured by measuring oxygen consumption (ml / kg / hr) in Sprague-Dawley lean male rats fed with cholesterol. After 2 weeks of feeding with cholesterol, the animals are given po
(oral) carrier or in increasing doses one of the compounds for a total of 7 days, then (at this time) oxygen consumption is determined. ED5 denotes the concentration of the compound, causing a decrease in metabolic rate by 5% compared with the carrier.

Claims (19)

1. The compound of the formula

Where X is oxygen (—O—); Y is - (CH ₂ ) _n -, where n is an integer from 1 to 3, or —C = C—, which is a cis or trans isomer; R ₁ denotes alkyl containing 3-6 carbon atoms; R ₂ and R _{3 are the} same or different and represent hydrogen, halogen, alkyl containing 1-4 carbon atoms, while at least one of R ₂ and R ₃ does not represent hydrogen; R ₄ is hydrogen or lower alkyl; R ₅ is hydrogen; R ₆ is a carboxylic acid or its ester; R ₇ is hydrogen; including all stereoisomers thereof or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, characterized in that R ₂ and R ₃ each independently represents halogen. 3. The compound according to claim 1, characterized in that R ₂ and R ₃ each independently represents alkyl. 4. The compound according to claim 1, characterized in that one of R ₂ and R ₃ is halogen, and the other is alkyl. 5. The compound according to claim 1, characterized in that one of R ₂ and R ₃ is halogen, and the other is hydrogen. 6. The compound according to claim 1, characterized in that one of R ₂ and R ₃ is alkyl, and the other is hydrogen. 7. The compound according to claim 1, characterized in that R ₂ and R ₃ independently represent Cl, Br, methyl or ethyl. 8. The compound according to claim 1, characterized in that R ₄ denotes hydrogen. 9. The compound according to claim 1, characterized in that R ₄ denotes methyl. 10. The compound according to claim 1, characterized in that Y is - (CH ₂ ) _n , where n is 1 or 2. 11. The compound according to claim 1, characterized in that Y is cis or trans ethylene. 12. The compound according to claim 1, having the structure

or

13. The compound according to claim 1, having the structure

or

14. The compound according to claim 1, having the structure

or

15. The compound according to claim 1, which is

16. A method for the prevention, suppression or treatment of a disease caused by metabolic dysfunction or dependent on the expression of T ₃ regulated gene, which consists in the introduction to a patient in need of treatment, a therapeutically effective amount of a compound according to claim 1. 17. The method according to clause 16, characterized in that the disease caused by metabolic dysfunction or depending on the expression of Tk of the regulated gene is obesity, hypercholesterolemia, atherosclerosis, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, glaucoma, cardiac arrhythmia congestive heart failure or skin lesion or disease. 18. The method according to 17, characterized in that the skin lesion or disease is dermal atrophy, post-surgical hematoma caused by laser exposure, keloids, atrophic skin strips, cellulite, roughened skin, photochemical skin lesion, lichen planus, ichthyosis, acne, psoriasis, Dernier disease, eczema, diffuse neurodermatitis, chloracne, pitiriasis, and scarring of the skin. 19. A method of treating a skin lesion or disease by using the compound according to claim 1 in combination with a retinoid or an analogue of vitamin D.